Division of Cellular Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
J Immunol. 2012 Aug 15;189(4):1773-9. doi: 10.4049/jimmunol.1201139. Epub 2012 Jul 6.
Leukocyte mono-Ig-like receptor 5 (LMIR5, also called CD300b) is an activating receptor expressed in myeloid cells. We have previously demonstrated that T cell Ig mucin 1 works as a ligand for LMIR5 in mouse ischemia/reperfusion injury of the kidneys. In this article, we show that LMIR5 is implicated in LPS-induced sepsis in mice. Notably, neutrophils constitutively released a soluble form of LMIR5 (sLMIR5) through proteolytic cleavage of surface LMIR5. Stimulation with TLR agonists augmented the release of sLMIR5. LPS administration or peritonitis induction increased serum levels of sLMIR5 in mice, which was substantially inhibited by neutrophil depletion. Thus, neutrophils were the main source of LPS-induced sLMIR5 in vivo. On the other hand, i.p. administration of LMIR5-Fc, a surrogate of sLMIR5, bound to resident macrophages (M) and stimulated transient inflammation in mice. Consistently, LMIR5-Fc induced in vitro cytokine production of peritoneal M via its unknown ligand. Interestingly, LMIR5 deficiency profoundly reduced systemic cytokine production and septic mortality in LPS-administered mice, although it did not affect in vitro cytokine production of LPS-stimulated peritoneal M. Importantly, the resistance of LMIR5-deficient mice to LPS- or peritonitis-induced septic death was decreased by LMIR5-Fc administration, implicating sLMIR5 in LPS responses in vivo. Collectively, neutrophil-derived sLMIR5 amplifies LPS-induced lethal inflammation.
白细胞单免疫球蛋白样受体 5（LMIR5，也称为 CD300b）是一种在髓样细胞中表达的激活受体。我们之前已经证明，T 细胞免疫球蛋白粘蛋白 1 作为 LMIR5 的配体在小鼠肾脏缺血/再灌注损伤中发挥作用。在本文中，我们表明 LMIR5 参与了 LPS 诱导的小鼠败血症。值得注意的是，中性粒细胞通过表面 LMIR5 的蛋白水解裂解持续释放可溶性形式的 LMIR5（sLMIR5）。TLR 激动剂的刺激增强了 sLMIR5 的释放。LPS 给药或腹膜炎诱导增加了小鼠血清中 sLMIR5 的水平，而中性粒细胞耗竭则大大抑制了该水平。因此，中性粒细胞是 LPS 诱导的体内 sLMIR5 的主要来源。另一方面，LMIR5-Fc（sLMIR5 的替代物）的腹腔内给药与驻留巨噬细胞（M）结合，并在小鼠中刺激短暂的炎症。一致地，LMIR5-Fc 通过其未知的配体诱导体外腹膜 M 的细胞因子产生。有趣的是，尽管 LMIR5 缺陷小鼠不影响 LPS 刺激的腹膜 M 的体外细胞因子产生，但它显着降低了 LPS 给药小鼠的全身细胞因子产生和败血症死亡率。重要的是，LMIR5-Fc 的给药降低了 LMIR5 缺陷小鼠对 LPS 或腹膜炎诱导的败血症死亡的抵抗力，表明 sLMIR5 在体内 LPS 反应中起作用。总之，中性粒细胞衍生的 sLMIR5 放大了 LPS 诱导的致命炎症。
